Regulation of T-lymphocyte recruitment by endothelial selectins and alpha4 integrins in pulmonary inflammation.

The recruitment of leukocytes during inflammation is mediated by cell adhesion molecules expressed on both leukocytes and endothelium of blood vessels in inflamed tissue. This study defined the relationship between cell adhesion molecules on the pulmonary vasculature and on leukocytes recovered from the lung parenchyma and air space during a delayed-hypersensitivity response to intratracheal (IT) sheep red blood cells (SRBC) in sensitized C57BL/6J mice. Silver-enhanced immunogold staining and RT-PCR of lung tissues revealed low constitutive expression of VCAM-1, E-selectin and P-selectin in normal lung vasculature, and sustained induction of these molecules throughout the lung for up to 7 days following pulmonary challenge with SRBC. Selectin-chimera binding studies on lymphocytes following IT SRBC challenge revealed that the number of selectin ligand-positive T-cells in the peripheral blood decreased rapidly, at the same time as these cells rapidly increased in bronchoalveolar lavage fluid and the lung interstitium. Interdicting adhesion pathways mediated by $\alpha$4 integrins or P-selectin resulted in a partial blockage of mononuclear leukocyte accumulation in lung three days after pulmonary challenge. In contrast, blocking L-selectin or $\alpha4$ integrins, or genetically deleting expression of all selectin ligands, had no effect on neutrophil accumulation in the lung one day after challenge. Lymphocyte trafficking was examined by infusing and tracking fluorescently-labeled T-cells in vivo during the SRBC-induced pulmonary immune response. Labeled cells recovered from the lung displayed ligands for E- and P-selectin in proportions significantly higher than that seen in the original infused populations. Blocking $\alpha$4 integrins or genetically deleting selectin ligand expression on labeled T-lymphoblasts resulted in $\sim$50% decrease in the cells' ability to traffic into inflamed lung. Combining these two treatments nearly ablated recruitment of the labeled T-cells. These studies determined that both $\alpha$4 integrins and P-selectin may mediate lymphocyte and monocyte accumulation during pulmonary inflammation. However, selectin interactions are not required for neutrophil recruitment into inflamed lung in response to SRBC. Trafficking studies in vivo demonstrated that the $\alpha$4 integrins and endothelial selectins independently contribute to T-cell recruitment into inflamed lung.PhDBiological SciencesCellular biologyHealth and Environmental SciencesImmunologyOncologyPathologyUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/130397/2/9722124.pd